PARP Inhibitors for Cancer Treatment

Poly (ADP-ribose) polymerase (PARP) are enzymes that attach polymers of ADP-ribose (PAR) to itself and other proteins. PARP play a role in DNA repair pathways; they act as sensors and initiate repair, preventing DNA mutation and allowing cellular survival after mitosis. DNA single strand break is involved in both repair pathways: the base excision repair (BER) and the nucleotide excision repair (NER). In DNA double strand break, is involved in the homologous recombination (HR) pathway (1).

If the PARP enzymes did not repair the DNA then the cancer cell would have too many mutations and so would trigger its own death. This is the premise by which PARP inhibitors were conceived as anti-cancer drugs.

PARP inhibitors (PARPi) bind to the catalytic site of the PARP enzymes, thus preventing normal enzymatic action. They attach the PARP enzymes at the DNA damaged moiety; this mechanism has been found to produce a greater cytotoxic activity than stopping the repair of single/double strand breaks (2). The breast cancer-associated protein (BRCA 1/2), alongside with PARP, participates in the homologous recombinational repair pathway. It has been shown that cells deficient in or with mutations in the gene coding to this protein are more sensitive than normal cells to the cytotoxic effects of PARPi (3). Because the PARPi decrease the ability of cells to repair themselves, these agents could be used as neoadjuvant agents sensitizing cancer cells in preparation for treatment by ionizing agents or conventional chemotherapy. They also could be used as monotherapy after other chemotherapy, (i.e. as adjuvant agents).

PARP inhibitors in clinical practice

PARPi are indicated for the treatment of ovarian cancer, fallopian tube, primary peritoneal and breast cancer. Rucaparib (Rubraca™) was the first PARPi approved by FDA in December 2016. Rucaparib is indicated as monotherapy for the treatment of patients with advanced ovarian cancer including harmful BRCA mutations (germline or somatic), who have been treated with two or three chemotherapies (4).

Niraparib (Zejula™) and Olaparib (Lymparza™) were approved in 2017. Niraparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy (5). Currently olaparib has three FDA indications for the treatment of adult patients. The first is in advanced ovarian cancer with deleterious germline BRCA mutations who have been treated with two or three chemotherapies. The second is in patients with epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. The third is in patients with deleterious or suspected deleterious germline BRCA mutation, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting (6).

The toxicity profile of PARPi is related to hematologic activity. Blood dyscrasias and fatigue are the most common adverse reactions. Clinical trial results suggest treatment-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) issues. PARPi should not be initiated if a patient has anemia or other blood dyscrasia. Data also shows no difference in the safety profile of PARP inhibitors in patients over 65 years old, compared to younger patients (7).

PARP inhibitors in research

Scientists are looking for new PARP indicators, and are searching for new uses/indications for known PARPi agents. No PARP inhibitor is approved as radio-sensitizing. However, combinations of PARPi with radiotherapy seem very promising. (9).

Prostate cancer is a focus of much PARP inhibitor research. PARP is activated by androgen receptor upregulation in prostate cancer; the combined treatment of bicalutamide and olaparib showed a synergic effect on suppressing tumor xenografts of C4-2 cells. This and other data suggest that the androgen deprivation treatment and PARP inhibitor combination could be an option for treatment of early stage castration resistant prostate cancer (8).